Structural Bioinformatics and Macromolecular Modelling
Full laboratory pages for Jim Warwicker's Group are at Warwicker group
We are developing models to calculate interactions within biological molecules and their complexes, thereby assessing contributions to structural stability and ligand binding energies. Model development looks to identify areas in which the physics and chemistry of macromolecular systems can be simplified whilst maintaining the detailed 3-dimensional information generated by structural studies. Recent effort has been directed towards improving prediction of pH-dependence through the introduction of a measure of rigidity/flexibility within proteins.
Theoretical work generates hypotheses for structure-function relationships that are used to interrogate the structural and genomic databases, giving predictions of protein redox activity, analysis of enzyme catalytic rate enhancement, and estimation of pH-dependence in both the folded and unfolded states. The Figure shows interactions with the dipole field of the modelled catalytic transition state of a phospholipase.
Models are now suitable for application to energy transducing systems, such as the molecular complexes of respiration and photosynthesis. We have also made predictions for various properties of prion proteins (PrPs), particularly pH-dependence of the C-terminal folded domain and the influence of an adjacent membrane. These have been linked to experimental collaborations, providing experimental design in collaboration with the partner groups. A broader interest concerns the molecular determinants of specificity and affinity for self-aggregating proteins and peptides across neurodegenerative diseases, and the implications for potential therapeutic agents.
BBSRC, Wellcome Trust, UKIERI